Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders in man, with an incidence rate of roughly 1 in 3,000 births. The study of how mutations and resulting alterations in cell function lead to the development of neurofibromas and other features of NF1 will require systems that can be experimentally manipulated. Damselfish neurofibromatosis (DNF), a disease affecting bicolor dameselfish is the only naturally occurring animal model of neurofibromatosis. This disease consists of plexiform neurofibromas and malignant schwannomas, many of which are hyperpigmented. DNF is caused by a transmissible, filterable agent. Cell cultures of tumor derived cells contain 100nm round particles and exhibit reverse transcriptase activity suggesting that DNF is associated with a retrovirus. The transmissible etiology of DNF results in a tumor model system that is easily manipulated in the laboratory. This research will emphasize characterization of the etiologic agent of DNF and the use of this agent as a tool to understand the pathogenesis of NF1 through five closely related research projects: 1) The morphology, nucleic acid content, protein composition, and reverse transcriptase activity of the viral particles associated with DNF (tentatively termed damselfish neurofibromatosis virus or DNFV) will be characterized. 2) Materials and methods will be developed to allow the detection of serum antibodies to DNFV as well as viral proteins and nucleic acids in tissues and in cultured cells from these fish. 3) The relationship between DNFV and neurofibroma development in these fish will be evaluated using transmission experiments in combination with probes developed in this study to screen for the presence of DNFV. 4) Studies of the pathogenesis of DNF will be continued and expanded using detection systems for DNFV as tracers of the cells types infected at various stages of spontaneous and experimentally induced tumor development. 5) Membrane properties of Schwann cells isolated from normal nerves and neurofibromas will be assessed and compared using electrophysiological techniques to determine if alterations occur during tumorigenesis or as a result of infection of Schwann cells with DNFV. If difference in ionic currents are found, pharmacologic techniques will be used to assess the involvement of GTP-binding protein mediated second messenger systems in these alterations. Information concerning alterations of membrane properties in neurofibroma derived cells should contribute to understanding of the axon- Schwann cell interaction and how this is altered during NF1 tumorigenesis. The usefulness of oncogenic viruses as experimenal tools for investigation of mechanisms of carcinogenesis has been well documented. The investigators believe that DNF will provide a useful experimental system to study the biology of neurofibromas and that their findings will be relevant to understanding the pathogenesis of NF1 in man.